An Interview on Mitochondrial Damage and Dysfunction in Aging

In this interesting interview, the topic is mitochondria and their role in aging. Mitochondria are the power plants of the cell, descendants of ancient symbiotic bacteria that still contain a small genome left over from that origin. Small it might be, but it is significant: stochastic damage to mitochondrial DNA (mtDNA) is one of the root causes of aging. Through a complex chain of events, this results a small but significant fraction of cells overtaken by mutant mitochondria and made to export harmful levels of oxidative molecules into surrounding tissues. This, to pick one example, produces oxidized lipids in the bloodstream that irritate blood vessel walls to start the inflammatory cascade that results in atherosclerosis. Quite aside from this process, however, mitochondria also undergo a general decline with advancing age, changing in many ways, and failing to keep up with their primary task of energy store production. This may be a reaction to other forms of damage in the tissue environment, and is particularly problematic in energy-hungry tissues like the brain and muscles.

Mitochondria, first and foremost, are these double membrane bound organelles that are in, essentially, all cells in your body. What makes them particularly interesting is that there are hundreds to thousands of them in each cell. The mitochondria produce the bulk of the ATP that you use every day, ATP is the energy currency of the cell. The other critical thing about mitochondria, is they have their own genome. You have your nuclear genome, where you got one copy from your mother, one from your father, but with respect to mitochondrial genomes, you have hundreds to thousands of them. Those are distributed among these organelles floating in the cytoplasm.

A final feature of mitochondria that turns out to be very important, they're not just static structures that sit in the cytoplasm like parked cars. They actually fuse with each other and then share contents and then they can also break apart, undergo fission. The sharing of components allows cells to, often times, maximize the amount of ATP that they want to produce. This turns out to have important consequences because it also does something else that's not so good, that defeats the ability to identify mitochondria containing mitochondrial DNA that is in some way mutant.

The way to think about this is the idea of quality control. The question is, mitochondria are always being generated, they have to work very hard, they create a lot of free radicals, a lot of damaging small molecules, and eventually they get turned over. So, even in non-dividing cells like muscle and neurons in your brain, the mitochondria are always being generated and then always being destroyed. That's important, because if you didn't get rid of these damaged mitochondria they would accumulate, and your cells wouldn't survive that, because they would lose the ability to generate energy.

The key issue with respect to quality control and mtDNA, and the fact that there are many mitochondria, or many mitochondrial genomes per cell, is that quality control may take a backseat, often times, to meeting more immediate cellular needs, like maximizing ATP production. Which is fine when you're young, but as you get older, and as that damage starts to accumulate, then you would really like it if quality control could kick in and do a bit of housecleaning.

We should think of mitochondrial DNA in a way, perhaps, still having its own selfish interests, left over from symbiosis. Because there is constant turnover, the mitochondria in you today aren't necessarily the ones that make you the most fit as an individual. They're the ones that survive this intracellular competition with other mitochondria and other mitochondrial genomes, the ones that have found a way to increase in frequency. The reason this relates to aging is that it turns out, as we age, we accumulate mutant mitochondrial DNA, such that, at some point, cells have so much mutant mtDNA that they either die or become otherwise dysfunctional. That leads to loss of function in critical tissues like heart, muscle, and the nervous system.

A very interesting question that we don't know the answer to is to figure out how it is that mutant genomes, in particular, deleterious genomes, seem to preferentially get amplified. There seems to be something a little bit haywire in cells, often, such that the quality control machinery, while it may exist, it doesn't get rid of the bad mitochondria with their mutant genomes. Those genomes have instead, found some way to increase in frequency and that then leads to a problem with aging.



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